1. Field of the Invention
This invention relates to compositions useful in the treatment of humans and other vertebrates infected with malaria parasites. More particularly, this invention relates to prophylactic and therapeutic compositions containing as active ingredients one or more substances that are toxic to the malaria-causing parasite alone or in combination with one or more substances that rescue the host vertebrate from the toxic effects of the anti-parasitic compositions. This invention also relates to the use of the aforementioned compositions for the prophylactic and therapeutic treatment of malaria in animal and human patients.
2. Description of Related Art
Malaria is a debilitating and often fatal disease caused by protozoans of the genus Plasmodium. According to World Health Organization estimates about 2.2 billion people live in areas in which malaria is still endemic, but control measures have decreased the level of toxicity; however, over 350 million people live in areas of the world in which malaria is highly endemic and no special antimalarial measures are being applied. "Science at Work: Special Programme for Research and Training in Tropical Diseases", UNDP/World Bank/WHO, Geneva, 2d ed., 1986.
Currently, quinine-based drugs, particularly chloroquine, are the mainstay of anti-malarial chemoprophylaxis, particularly for those species for Plasmodium that are sensitive to this drug, i.e., P. knowlesi, P. vivax, P. ovale, P. malariae, P. yoelii and cloroquine-sensitive P. falciparum [Herwaldt, B. L., et al., Antimicrob. Agents Chemotherap., 32:953 (1988); Krogstad, D. J., et al., Id., p. 957]. There are several important problems attendant upon the use of chloroquine as an anti-malarial. Although oral chloroquine typically is well-tolerated, some patients experience serious side effects. In addition, the safety of parenteral chloroquine has been questioned because it may cause cardiac arrhythmia and sudden death in children. Krogstad, et al. 1988 at 957. Further, P. falciparum strains resistant to chloroquine and other traditional drugs are known in at least 40 tropical and subtropical countries [Payne, D., Parisitol. Today, 3:241-5 (1987); Wyler, D. J., N. Eng. J. Med., 308, 875 (1983)]. In areas with chloroquine-resistant P. falciparum, combination therapies have been recommended (chloroquine plus pyrimethamine-plus-sulfodoxine), but the latter components are known to cause severe, even fatal, reactions [Herwaldt et al. 1988, at 953]. Furthermore, correlations between the in vitro suspectibility of parasites to chloroquine, mefloquine or other anti-malarial agents and clinical effectiveness are known to be very imprecise, and are more qualitative than quantitative [Herwaldt et al. 1988, at 953]. The future of malarial chemotherapy is particularly alarming in view of parasite strains that display cross-resistance to several structurally unrelated drugs [Hubbert, T. E., et al., 35th Ann. Mtg. Amer. Soc. Trop. Med. Hyg., Denver, Colo., 1986; Webster, H. K., et al., Am. J. Trop. Med. Hyg., 34:228-35 (1985)].
Thus, it is important to develop novel antimalarial drugs, particularly those that are effective against strains of malaria-causing parasites that display single or multiple drug resistance.
The erythrocytic phase of the life cycle of P. falciparum is associated with clinical symptoms of malaria. During this 48 hour asexual cycle, each parasite inside a red blood cell generates 6 to 24 offspring that burst out and individually invade fresh erythrocytes. The exponential increase in parasites requires a steady supply of purine and pyrimidine nucleotides for the DNA and RNA synthesis necessary for their growth. Malarial parasites are able to use the rich pool of adenine nucleotides inside the erythrocytes to obtain their supply of purines, but these parasites, lacking the "salvage" pathway, cannot use preformed pyrimidines and, thus, must synthesize them de novo [Sherman, I. W., et al., Microbiol. Rev., 43:453-96 (1979); Reyes, P., et al., Mol. Biochem. Parasitol., 5:275-90 (1982); Rathod, P. K., et al., J. Biol. Chem., 258:2852-5 (1983)]. In contrast, mammalian cells are able to utilize preformed pyrimidine bases and nucleosides by salvage pathways [Jones, M. E., Ann. Rev. Biochem., 49:253-79; Moyer, J. D., et al., J. Biol. Chem., 260:2812-18 (1985)].
These distinctions in pyrimidine metabolisms between malaria parasites and the cells of host mammals have led to the present discovery of anti-malarial prophylactic and therapeutic compositions that are lethal to such parasites, but not toxic to the host vertebrates harboring these parasites.